N-(aminoalkyl)-2-alkoxy-phenoxazines and a method of making n-(aminoalkyl)-phenoxazine derivatives



111 R1 @IQ Big United States Patent N -(AMINOALKYL) 2 ALKOXYPHENOXAZINES AND A METHOD OF MAKING N-(AMINOAL- KYL)-PHENOXAZINEDERIVATIVES Guido Eros Bonvicino, Pearl River, N.Y., and Robert AllisHardy, Jr., Ridgewood, and Lawrence Henry Yogodzinski, Hillsdale, N.J.,assignors to American Cyanamid Company, New York, N.Y., a corporation ofMaine N0 Drawing. Filed Oct. 25, 1961, Ser. No, 147,464

3 Claims. (Cl. 260-244) This application is a continuation-in-part ofour copending application Serial No. 832,175, filed August 7, 1959, nowabandoned.

This invention relates to certain N-(aminoalkyl)-2- alkoxy-phenoxazinesand to a novel method of preparing substituted N (aminoalkyl)phenoxazine derivatives. More particularly, the invention is concernedwith novel compounds which may be represented by the following generalformula:

Ra CHZCHZCHZ-N I /N\ R; OR

wherein R is lower alkyl and wherein R and R are each hydrogen, halogen,lower alkyl lower alkoxy or trifiuoromethyl with the proviso that R andR cannot both be hydrogen;

3,2l5fi92 Patented Nov. 2, 1965 ice is :di(lower alkyl)-amino,N-methylpiperazino, piperidino, =morpholino or pyrrolidino; X isreactive halogen and n is an integer greater than 1 and less than 5.Suitable lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl,N-butyl, etc. Suitable lower alkoxy substituents are, for example,methoxy, ethoxy, n-propoxy, iso-propoxy, etc. Reactive halogen isexemplified by chlorine and bromine.

The novel N-(amnioalkyl)-2-alkoxy-phenoxazines of the present inventionform non-toxic acid addition and quaternary ammonium salts with avariety of organic and inorganic salt forming reagents. Thus,acid-addition salts, formed by admixture of the organic free base withan acid, suitably in a neutral solvent, are formed with such acids assulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric,lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbicand related acids. For purposes of this invention the free bases areequivalent to their non-toxic acid-addition salts.

The novel compounds of the present invention are, in general, whitecrystalline solids. They are generally insoluble in water, butrelatively soluble in organic solvents such as lower alkanols, esters,ethers, ketones, benzene, toluene, chloroform, and the like. Theacid-addition salts of the organic bases of the present invention are,in general, crystalline solids, relatively soluble in Water, methanoland ethanol, but relatively insoluble in non-polar organic solvents suchas ether, benzene, toluene and the like.

The novel compounds of the present invention are central nervous systemdepressants of the tranquilizer or tranquilizer-muscle relaxant type.Upon administration they produce a sedative action with few side effectsand are particularly valuable (in contrast to the more potenttranquilizing drugs) in mild cases of mental and emotional upset as wellas somatic disorders requiring relaxant agents with little danger ofserious side effects. The dosage required to produce the aforementionedeffect varies between about 50 mg. and 500 mg. per individual dose. Thedosage regimen may be adjusted to provide the optimum therapeuticresponse. For example, several doses may be administered daily or thedose may be proportionately reduced as indicated by the exigencies ofthe therapeutic situation.

The novel process of the present invention provides an important newmethod for the preparation of substituted N-(aminoalkyl)-phenoxazineswhich are well-known as useful tranquillizing agents and which have beendescribed in US. Patents 2,947,745 and 2,947,747 to Craig, and byOlmstead et al., J. Org. Chem., 26, 1901 (1961), and by Bonvicino etal., J. Org. Chem., 26, 2797 (1961). The novel process of the presentinvention is particularly advantageous in that very high yields of thedesired N-(aminoalkyl)-phenoxazines are obtained in an excellent stateof purity by the ring closure of an appropriately substituted 2 [ohalo-N-(disubstituted-aminoalkyl)anilino]phenol.

The ring closure of the anilinophenol derivative is achieved bytreatment with a basic condensing agent and a metal catalyst in an inertorganic solvent. Suitable basic condensing agents are the alkali oralkaline earth carbonates such as sodium car-bonate, potassiumcarbonate, lithium carbonate, magnesium carbonate, and the like.Suitable metal catalysts are transition metals such as copper, silver,nickel, zinc, and the like. Copper powder is particularly useful andcopper salts such as copper sulfate, cupric acetate, and the like arealso suitable. The inert organic solvent is not critical but isconveniently used as a diluent. High boiling solvents in which thereactants are at least partially soluble are particularly desirable.Suitable solvents include dimethylformamide, diethylformamide,diethylacetamide, ethylene glycol dimethylether, and the like, The ringclosure is generally carried out at an elevated temperature,conveniently the refluxing temperature of the solvent. Temperatures offrom 125 C. to 200 C. are suitable but the preferred temperature rangeis from about 140 C. to about 150 C. Heating is continued until thereaction is substantially complete, generally from about 24 to about 48hours. The reaction product may be readily obtained simply byevaporation of the inert organic solvent. When the solvent iswater-soluble, such is dimethylformamide, a particularly usefultechnique is dilution of the reaction mixture with a large excess ofwater followed by extraction of the reaction product into ether.Evaporation of the ether extract gives the desired phenoxazine base inexcellent yield and a good state of purity. Further purification of thephenoxazine base may be achieved by distillation under reduced pressureor by the recrystallization of acid addition salts of the base.

It is a particular advantage of the present invention that a widevariety of substituents on the aromatic rings may be employed. Manyprevious phenoxazine syntheses have been limited by the need for specialactivating groups or are just not applicable for certain classes ofsubstituents on the aromatic rings. For example, the methods describedby Craig in US. Patents 2,947,745 and 2,947,747 cannot be employed fornuclear lower alkoxy substituents. Such compounds, however, are readilyprepared by the novel process of the present invention.

Another advantage of the novel process of the present invention residesin the fact that special blocking groups on the oxazine nitrogen atomare not required during the ring closure. Heretofore, a number ofphenoxazine syntheses have required the introduction of blocking groupson the oxazine nitrogen atom in order to achieve good results during thering closure. These blocking groups must necessarily be removed beforethe phenoxazine derivative may be converted to the desired N.(aminoalkyl)-phenoxazine. Thus, the novel ring closure of the presentinvention is widely applicable to a variety of nuclear substitutentswithout the necessity of introducing and subsequently removing oraltering extraneous blocking or activating groups.

The appropriately substituted2-[O-halo-N-(di-substituted-aminoalkyl)anilino]phenols, employed asstarting materials in the ring closure step, are obtained in good yieldsand in an excellent state of purity by the novel rearrangement of thecorresponding N-[2-(o-halophenoxy) phenyl]-N',N-disubstituted-alkylenediamines. The rearrangement of thehalophenoxyphenyl alkylenediamine derivatives is achieved by treatment,in an inert organic solvent, with a base capable of forming a nitrogenanion. Suitable bases for eifecting the rearrangement include sodium,potassium, and lithium amides, sodium hydride, butyl lithium, dimethylmagnesium and the like. At least one molecular equivalent of the baseforming reagent is employed. The inert organic solvent is not criticaland solvents such as benzene, toluene, xylene, and the like may be used.Rearrangement is conveniently carried out at the refluxing temperatureof the solvent. Temperatures of from 25 C. to 150 C. are suitable butthe preferred temperature range is from about 75 C. to about 120 C.Heating is continued until the rearrangement is substantially complete,generally from about 6 to about 24 hours. The rearrangement products arereadily isolated from the reaction mixture as phenolate salts which, insome cases, precipitate directly from the reaction mixture in a goodstate of purity. The anilinophenols may be readily obtained from theirphenolate salts simply by trituration with water. They form acidaddition salts and may be characterized and purified in this manner.

A further advantage of this novel rearrangement of the present inventionresides in the fact that it may be carried out either withN-[2-(o-halophenoxy)phenyl]- N, N-disubstituted-alkenediamines or withproducts which are prepared in situ. Bythis variation, appropriatelysubstituted O-halophenoxyanilines are treated with an appropriateN,N-disubstituted-aminoalkyl halide and an excess (two molecularequivalents or more) of the basic condensing agent under the conditionsdescribed above whereby the corresponding anilinophenols are obtaineddirectly in good yields. This eliminates the necessity of isolation ofintermediate compounds and facilitates the ultimate obtention of the endproducts, the N-(aminoalkyl)-phenoxazine derivatives, by a practical andeconomically feasible series of steps. This variant of the rearrangementstep and the preparation of the necessary intermediates is set forth inthe following reaction scheme:

X N O2- R1 R2 --ONa XV lheat X N O 2 R11 i SEC/l2; H01

X N Hz Yh R1 I B2- NaNH o (2 moles) sR4 N RsRA A} NaNHz (IJ u Qn mole)11 211 1 (11 Ba R4 R3 R4 v N t nHzn n Zn l N X NH X HO 0/ This reactionscheme shows the most economical products; for example, the phenolatesare shown as sodium phenolates and the disubstituted-aminoalkyl halidesas the chlorides. This is no sense necessary as the potassium phenolatesare just as effective and othed disubstituted-aminoalkyl halides such asthe bromides may be employed. However, because the more expensiveproducts do not present any advantages, the sodio and chloro compoundsare preferable. In similar manner, sodamide may be replaced by potassiumamide but as there is no advantage and the cost is higher, we prefer touse the cheaper material and have so illustrated in the reaction scheme.

Insofar as the preparation of the intermediates is concerned, thevarious reactions present the usual problems of organic chemicalsynthesis. They are best carried out in inert reaction media and forthis purpose typical organic liquids such as ether, lower alk-anols,benzene, dimethylformamide, and the like are useful and are illustratedin the specific examples below. The invention is, of course, not limitedto the use of these particular reaction media and other reaction mediahaving satisfactory inertness, solvent characteristics, and boilingpoints may be used. Thus, for example, toluene may replace lbenzene,isopropanol may replace ethanol, etc. Similarly some of the steps arecarried outat elevated temperatures. The examples set forth thepreferred temperature or temperature range in each case. The examplesalso include various standard purification processes, such as Example2.-2-(0-halophenoxy)aniline derivatives recrystallization fromwell-known recrystallizing solvents. Br NH: They are intended to beillustrative only and other solvent 01 systems may be employed.

The invention will now be described in greater detail in 5 \O/conjunction with the following specific examples in which the parts areby weight unless otherwise specified. A mixture of (0-02 mole) ofo'bromophenyl'4' chloro-2-nitrophenyl ether and 18.1 g. (0.02 mole) ofstannous chloride dihydrate in 200 ml. of ether under reflux andstirring is treated with a slow stream of anhydrous Example1.0-Hal0phenyl-2-nitr0phenyl ether derivatives 10 Br NO: hydrogenchloride for three hours. The reaction mix- C1 ture is evaporated todryness, suspended in a 150-200 ml. mixture of water and ice and madestrongly alkaline with \o/ 40% sodium hydroxide until the precipitatedinorganic The cooled reaction mixture is extracted with ether. Theethereal extract is washed with water until the washings are no longeralkaline. It is dried over anhydrous magnesium sulfate, evaporated todryness, and the residue distilled under reduced pressure.

The product, 2-(o-bromophenoxy)-5-chloroaniline, is collected andconverted to the hydrochloride salt in ether by the addition ofanhydrous hydrogen chloride. The product is then purified byrecrystallization from an alcoholether mixture.

The above procedure is repeated with other starting materials, preparedby the method of Example 1, in each case using the stoichiometricequivalent. The starting materials and products are shown in thefollowing table: TABLE II 15 bases redissolve.

A solution of 10.8 g. (0.2 mole) of sodium methylate, 34.6 g. (0.2 mole)of o-brornophenol and 38.8 g. (0.2 mole) of l,4-dichloro-2-nitrobenzenein 200 ml. of ethanol is evaporated to dryness in vacuo on a steam bath.The residue is heated at 160-165 C. for two hours and cooled. Theproduct is suspended in 200 ml. of 10% sodium hydroxide and extractedwith ether. The ethereal extract is dried over anhydrous magnesiumsulfate and evaporated to dryness. The residue is exaustively extractedwith boiling petroleum-ether (B.P. 90l00 C.). The crystalline productseparates from the petroleum ether extract on cooling, is collected andrecrystallized from ethyl acetate-petroleum ether. The product iso-bromophenyl-4-ch1oro-2-nitrophenyl ether.

The procedure of the above example is repeated with other reactants, ineach case using the stoichiometric equivalent. The reactants andresulting products are shown in the following table:

Starting Materials Products o-Bromophenyl-4-methoxy-2-nitro-6-(o-Bromophenoxy)-mphenyl ether.

anisidine.

o-Bromophenyl-Q-nitro-p-tolylether G-(g-Bromophenoxy)-m-t0lui- TABLE I-B h -5-hl h 12-- h Starting Materials Products 0 ettitliemnop enyl eera 2 nitrop eny gingirlpglop enoxy) 4 chloro o-Bromophenolt-ethlgroe-niiroa- O-:tBlfD1m0ph2Gnytl-|X,D,Cl- Example3.-N'-[2-o-hal0phen0xy)phenyl] -N,N-

' t n 0- -n' I 0 e g g 1 To p dlsubstztuted-I,3-pr0panedzammes CH3 CH0-Br0m0pheuol 4-chl0ro-3-nitr0anrsole.o-Bromophenyltmethoxy-Z-nitrophenyl N ether. ([3 2)a o-Brorn0phenol.4-ehl0ro-3-n1trotoluene. 0-Brorn0phenyl-2-n1trop-tolyl ether. Br NHo-Bromophenol 2,4-dichloronitrobeno-Bromophenyl-5- O1 zene.chloro-Z-nitrophcnyl ether.

TABLE III Starting Materials Products 2-(0-brom0phcnoxy)-5-l-(3-chloropropyD-4- 1-{3-[2-(o-bromophenoxy)-5-chloroanilino]-chloroauiline. mcthylpiperazine. propyl] -4-m0thylpiperazine.

2-(o-br0in0pl1enoxy)-4- 3-chloro-N,N-dimethyl- N -[2- (o-bromophenoxy)-4-chlorophenyl1- ehloroaniline. propylamine. N,N-dimethy]-1.3-propanediamin e.

o-(2, tdibromophenoxy)- 3-chloro-N,N-dirnethyl- N2,4-dibromophenoxy)phcuy1]-N,N-

aniline. propylamine. dimcthyl-l ,3-propauediamine.

6-( o-brornopl1enoxy)-m- 3-chl0r0-N,N-dimethyl-N-[2-(o-bromophcnoxy)-5-methoxyphenyl1- anisidine. propylamine.N,N-dimethy1-1,3-propanediamiue.

6-(0-hrorn0phen0xy)-m- 3-ehloro-N ,N-dimethyl- N-'6-(o-brom0phenoxy)-m-t0ly1]-N,N-

toluidiue. propylamine. dimethyl-l ,3-propanediamine.

6-(o bromophenoxyl-ma,a- 3-chloro-N,N-dimethyl- N-[6 (o-brorn0phenoxy)-a,a,a-trifiuoro-mtrifluoro-m-toluidlne. propylamine. tolyl]-N,N-dimethyl-l ,3-propanediami no.

piperazine.

toluidin01propyl] -4-methylpiperazine.

2-(o-br0mophenoxy)-5- chloroaniline.

4-(2-chloroethyl)-morpholine.

2- (o-bromophenoxy) -5- chloroaniline.

3-ohlor0-N ,N-2-trimethylpropylamine.

N -[2'(0-bromophenoxy) -5-chl0rophen yl]-N,N-Z-trirnethyl-l,3propanediamine.

6(0-bromophenoxy)-manisidine.

N- (3-ehloropropyl) dibutylamine.

N -[2-(o-brornophen0xy)-5-mcth0xyphenyl] N ,Ndibutyl-1,3-propanediamine.

7 A mixture of 66.0 g. (0.22 mole) of 2-(o-bromophenoxy)-5-chloroanilineand 10.8 g. (0.25 mole) of sodium amide (90% technical, in mineral oil)in 400 ml. of

stoichiometric amounts of other reactants. The reactants and productsare shown in the following table:

TABLE IV anhydrous benzene is refluxed with vigorous stirring for 2.5hours. A solution of 30.4 g. (0.25 mole) of 3-chloro- 5 StartingMaterials Products N,Nd1methy1propylam1ne 1n 100 ml. of anhydrousbenzene is added dropwise and refluxing is continued for 18 N lfi (obmmophenoxy) ayW4 2 [o bromo N (3 dimethy1a hours. The cooled reactionmixture is filtered to remove -gq y l y jg p py i l-mm the precipitatedinorganic salts. The filtrate is evaporated lg'propane lamme' nuoro'p'creso to dryness, the residue is dissolved in ether, and thesolu- 10 -g p p g rpg t1 1 p g gpg i otion is extracted with 400 ml. of1 N-hydrochloric acid. if igig flfi ifgnkna mm W- $52 331? oHrme oxy-The aqueous acidic extract is neutralized with an excess of N, r) 4 db hz 2 4 (Yb N 3 th 1 potassium carbonate and extracted with ether. The;{1;Q; Z F2E H ggg ggfgg 1 g,;, ethereal extracts are combined, driedover anhydrous magpwpanediamine- 1165mm Sulfate; and evaporated to y TheP 5 N'-[6-(o-hromophenoxy)m-tolyl]- 2-[o-br0mo-N-(3-dirnethylamino- N [2(o-bromophenoxy)-5 chlorophenyl]-N,N-dimethy -p p p py ml-pyl-l,3-pnopanediamine, is obtained by distillation under reducedpressure. The dihydrochloride precipitates from a p e y)- -N- yaminosolution of alcohol and ether on treatment of the base giggglgggfigflgf prowl)amhnol'5'cmomphenol with two equivalents of alcoholichydrogen chloride.

- -N-4- h-- The procedure of the above example is repeated uslng 1 fi gg REEfiKEEfiQS QT 'g fiffirl lif fifignifiio stoichiometric amounts ofother reactants. The reactants mfithylpiperezineand Products pp in thetable above- 1-{3-[2-(o-brompphenoxy)-5- 2-lo -brom0-N-[3-(4-methyllmethoxyaurhuo]-pr0pyl -4- p1peraz1nyl)-propyl] aniline -4- Example4.--2-[0-hal0-N-(3-disubstituted-aminopropyl) methylpiperazinemethoxyphelwlanilino Phenols 4- {2-[2- (o-bromophenoxy)-5- 2-[0-bromo-N-(2-morpholinoethylchlor0anilin01-ethyl}morpholine. ani1ino]-4chlorophen0l. 0&3 N-[2-(o-bromophenoxy)-E 2-[o-hromo-N-(3-dimethylamino-N chlorophenyl]-N,N,2-tr1methyl- 2-rnethylpr0pyD-amhno1-4-1,3-pr0panediamine. ehlorophenol. I H2)? N'-[2-(o-bromophenoxy)-5- v2-[o-bromo-N-(3-dibutylamino- N methoxyphenyH-N,N-dibutyl--propyl)anilin0]-4-methoxy- C1 1,3-propaned1amme. phenol,

\ Example 5 Br H0 I The product of Example 4 is produced in excellentyield -b the method of Exam 1e 3 accordin to the followin A mlxture of(Q0292 pi ocess in which the am unt of sodami de used is at lea-s?phenoxy) 5 chlorophenyl] N,N-d1methy1-1,3-propanetwice ,stoichiometric'P 9 '2 1? 2 sodlum amlde (90% 36.2 .g. (0.121 mole) of2(o-bromophenoxy)-5-chlort meal g g m fi w benzne aniline and 21.0 g.(0.485 mole) of sodium amide (90% 2 e ed Ramon technical, in mineraloil) in 350 ml. of anhydrous ben- "P 1S i t P Crude Product (Insolublefrac zene is reacted with 14.7 g. (0.121 mole) of 3-chloro-N, tion)saved. e trate is evaporated to dryness and. the Ndimethylpmpylamine in75 of anhydrous benzene resldfle trfturated h cold 6 The sohd Product soas described in Example 3. The insoluble reaction prodobtamed 1s pooledwith the crude product and suspended not, as the f Phenolic derivative 2J 3 i 111 100 of Water. StIIT'ed 15 mlmltes, f collectedmethylam-inopropyl)anilinol -4-chlorophenol, .is obtained y filtratlon-Recrystalllzatlon the Preclpltate from in 82.5% yield and is purified asdescribed in Example 4. ethanol, 1 y elves Analyt-ically pure materialis obtained after onerecrystalmethylarmnopropyl)an1l1no]-4-chlorophenol. When the lizationfrom alcohol without -a substantial change in mclt crude product,described above, is recrystallized from aning point. hydrous ethanolwithout triturating with water, the sodium The above procedure isrepeated with stoichiometr-ic salt is obtained. quantities of otherreagents. The reagents and the prod- The procedure of the above exampleis repeated with ucts obtained are shown in the following table:

TABLE V Starting Materials Products 2-(0-bromophen0xy)-5- 'lin1-(3-chloropropyl)-4- 2- l0-bromo-N-[3-(4-methy1-1-piperazinyl) chloroame. methylpiperazine. propyl]-ani1ino} -4-chl0rophenol.

2-(o-brom0phenoxy)-4- 3-chloro-N,N-dimethyl-2-[o-bromo-N-(3-dimethylaminopropyl)- chloroaniline. propylamine.anilin0]-5-ehl0rophenol.

o-(2,4-dibromophenoxy)- 3-chloro-N,N-dimethyl-Z-[ZA-dibromoN-(3-dimethylaminopropyl)- aniline. propylamine.anilin0]-phenol.

6-(o-brom0phenoxy)-m- 3-chloro-N,N-dimethyl-2-[o-bromo-N-(3-dimethylaminopropyl)- anisidine. propylamine.anilino]-4-methoxyphenol.

G-(o-bromophenoxy) -mtoluidine.

3-chloro-N,N-dimethylpropylamine.

3-ehloro-N,N-dimethyl- 2-[o-bromo-N-(3-dimethylaminopropyl)- Example 6.1 -(3-disubstituted-aminopropyl phenoxazines CH2CHz 2 M A mixture of9.6 g. (0.025 mole) of 2-[o-bromo-N-(3- dimethylaminop-ropyl)anilin'o] 4--chlorophenol, 4.6 g. (0.033 mole) of potassium carbonate and 1.0 g. ofcopper powder in 100 ml. of N,N-dimethylformamide is heated under refluxfor 48 hours. The cooled reaction mixture is filtered and the filtrateis evaporated to dryness under vacuum. The residue, 8.5 g., is dissolvedin 100 ml. of ether, washed with water, and dried over anhydrousmagnesium sulfate. Evaporation of the ethereal solution aifords 7.0 g.(92% yield) of substantially pure free base to give 81% yield of thehydrochloride after two recrystallizations from alcohol-ether. Analternate method of purification is to treat'the filtered reactionmixture with a large excess of water, followed by extraction with ether.The ethereal extract is dried, evaporated to dryness, and the residue isthen converted directly to the hydrochloride salt.

The above procedure is repeated with stoich-iometr-ic amounts of otherstarting materials. The starting materials and products so obtained areshown in the following table:

TABLE VI Starting Materials Products -(3-dimethylaminopropyl)-2-2-[o-bromo-N-(3-dimethylam inomethoxyphenoxazinc.

pr'opyl) anilinoli-methoxyphenol.

2-lo-bromo-N-[3-(4-methyl-lpiperazinyl)-propyl]ani1ino}-4-methoxyphenol.

2-metl1oxy-10-[3-(4-methyl-1- piperazinyDpropyl]phenoxazinc.

4-ohloro-10-(3-dimethylaminopropyD-phenoxazine.

2-chlor0-10-[3-(4-rnethyl-1-piperazinyl)-propyl]phenoxazine.

2-[o-bromo-N-(3-dimethylaminopropyl) anilin0]-6'ch10ropheno1.

2-lo-brorno-N-[3-(4-methyl-lpiperazinyl) -propyl]anili.nol A-chlorophenol.

10-(B-dimethylaminopropyl)-2- methyl-phenoxazine.

10-(3-dimethylaminopropyl)-2-trifiuoromethylphenoxazine.

2-[o-bromoN-(3-dimethylaminopropy1)auilino]-p-cresol.

2-[o-bromo-N-(3-dimethylaminopropyl)anilino]-a,a,m-trifiuorop-oresol.

What is claimed is: 1. The process of preparing compounds of theformula:

is selected from the group consisting of di(lower alkyl)- 1G amino,morpholino and N-lower alkylpiperazino, X is halogen, and n is aninteger greater than 1 and less than 5; which comprises heating in aninert solvent at a temperature of from about 25 C. to about C. acompound of the formula:

R1 I R2 wherein R R and X are as hereinabove defined, with a compound ofthe formula:

XHO

wherein R and R are each selected from the group consisting of hydrogen,halogen, lower alkyl, lower alkoxy and trifiuoromethyl with the provisothat R and R may not both be hydrogen,

is selected from the group consisting of di(lower alky1)- amino,morpholino and N-lower alkylpiperazino, X is halogen, and n is aninteger greater than 1 and less than 5; which comprises heating in aninert organic solvent at a temperature of from about 25 C. to about 150C. a compound of the formula:

R4 a... X H1 1 wherein R R X and n are as hereinabove defined, in thepresence of at least about one molar equivalent of a nitrogen anionforming reagent selected from the group consisting of alkali metalamides, alkali metal hydrides and metalloorganic compounds.

11 3. The process of preparing compounds of the formula:

wherein R and R are each selected from the group consisting of hydrogen,halogen, lower alkyl, lower alkoXy and trifluoromethyl with the provisothat R and R may not both be hydrogen,

is selected from the group consisting of di(lower alkyl)- amino,morpholino and N-lower alkylpiperazino, and n is an integer greater than1 and less than 5; which comprises heating in an inert organic solventat a temperature of from about 25 C. to about 150 C. a compound of theformula:

wherein R R References Cited by the Examiner UNITED STATES PATENTS2,769,002 10/56 Buiss'on et al. 2,945,031 7/60 Gordon 260243 2,947,7478/60 Craig 260-444 FOREIGN PATENTS 201,628 10/ Australia. 231,954 2/59Australia.

OTHER REFERENCES Brady et al., J. Chem. 800., pages 1218-22 (1930).Rodd, Chemistry of Carbon Compounds, volume We, pages 1494-6 (1960).

WALTER A. MONDANCE, Primary Examiner.

DUVAL T. MCCUT CHEN, IRVING MARCUS,

Examiners.

3. THE PROCESS OF PREPARING COMPOUNDS OF THE FORMULA: 